FI84829B - FOERFARANDE FOER FRAMSTAELLNING AV CEFODIZIM. - Google Patents

Abstract

A process for the preparation of cefodizime of the formula <IMAGE> +TR <IMAGE> wherein (a) a compound of the formula II (ATS) <IMAGE> wherein R1 represents hydrogen or an aminoprotective group and A represents a hydrogen atom or one equivalent of an alkali metal or alkaline earth metal, of ammonium or of an organic nitrogen base, is first reacted with a compound of the formula III R-SO2Hal wherein R represents an optionally substituted alkyl, aryl or aralkyl radical and Hal represents a halogen atom, in an organic solvent and, if appropriate, in the presence of a base, (b) a compound of the formula I (TACS) <IMAGE> in which A has the above meaning, is reacted with a silylating agent in an organic solvent and, if appropriate, in the presence of a base, and (c) the two products formed in (a) and (b) are reacted in their reaction solutions, and any protective group R1 present in the end product of the formula I is eliminated.

Description

V

1 84829

Method for the preparation of Cefodizlm

The invention relates to a process for the preparation of Cefodizlm of formula 5

2 XOCH * 2 6 CH - COOH

1Q °° Μ3 COOH 2 (Cefodizim)

Cefodizim (HR 221) is an antibiotic whose preparation and good antibiotic effect are known in the literature. It can be obtained by administering an ATS having an activated carboxyl group of the formula xxr ~

H N 5 H

20 2 \

OCH

(ATS) to react with a TACS of 25: 3 °

COOH

(tacs): 35 2 84829

A particularly preferred process for the preparation of cephalosporins is described in EP-A-23 453. However, when used for the preparation of Cefodizim, in addition to the desired Cefodizim, by-products of the order of about 5-15% are formed. The concentration of the by-product can be reduced by various successive purification steps, but it cannot be completely removed from Cefodizim. In addition, these purification methods (e.g., chromatography, recrystallization) are costly because they are thorough and significantly reduce the overall yield.

Therefore, a considerable number of experiments have been performed to modify the reaction parameters in order to prevent the formation of a by-product, such as by changing the molar ratios, temperature, reaction time, solvent, optionally added base, activator or other additives. None of these experiments have yielded results. The formation of said by-product has not been reduced.

In the study of other additives, it has now been found that the addition of a silylating agent to the TACS almost completely prevents the formation of a by-product.

The invention thus relates to a process for the preparation of Cefodizim having the formula:: 25 λΤτ ^ τϊ ^ -.

* © OOH 2 (Cefodizim) 35 The process according to the invention is characterized in that 3 84829 (a) first a compound of formula II (ATS)

N-j-C-COOA

Wherein Rx represents hydrogen or an amino protecting group and A represents hydrogen or one equivalent of an alkali or alkaline earth metal, ammonium or an organic nitrogen base, is reacted in an organic solvent and optionally in the presence of a base with a compound of formula III R -SO 2 -Hal, where R is p-tolyl or phenyl and Hal is chlorine, (b) a compound of formula I (TACS) 20 II-f "3

i-N ^ A ~ CH2S S -A

0 C00A CH2-C00A

Wherein Ailia is as defined above, is reacted with an silylating agent in an organic solvent and optionally in the presence of a base, and c) the products formed according to both (a) and (b) are reacted in their reaction solutions and the protecting group Rx in the reaction product is cleaved. off.

In addition to hydrogen or ammonium, A can also denote one equivalent of an alkali metal, such as sodium or potassium, an alkaline earth metal, such as calcium or magnesium, or an organic nitrogen base, such as di- 4,84829 ethyl, trimethyl, triethyl, methyl, propyl, N, N-dimethylethanol or ethanolamine.

Suitable protecting groups Rx are those described as amino-protecting groups in the field of cephalosporin or peptide-5 chemistry, for example those mentioned in EP-A-23453, p. 3, lines 43-63. Compounds in which Rx is hydrogen are preferred. Thus, protection of a non-essential amino group can save two reaction steps (protection, deprotection), which leads to a further increase in yield.

The reaction between a compound of formula II and a compound of formula III may be carried out in an anhydrous organic solvent such as acetone, ethyl acetate, tetrahydrofuran, acetonitrile, tetrachloromethane, methylene chloride, toluene, dioxane, pyrrolidine, isopropyl ether, N-methyl ether, N-methyl ether , however, preferably in dimethylacetamide at temperatures between -30 and 0 ° C, preferably between -10 and -15 ° C.

If the compound of formula II is used in the form of the free acid (A = hydrogen), it is expedient to add a base, preferably an organic nitrogen base, such as triethylamine, N, N-dimethylaniline, tributylamine, N-methylmorpholine, pyridine, picoline-25 or also, for example, sodium or potassium carbonate or bicarbonate, preferably triethylamine. The addition of a base can be dispensed with if the carboxylic acid of the formula II is used in the form of one of the abovementioned salts.

The further reaction is then carried out by reacting a compound of formula I (TACS) in an anhydrous organic solvent such as, for example, methylene chloride, dimethylacetamide, methyl tert-butyl ether, methyl isobutyl ketone, butyl acetate 8 or especially methyl acetate, 35 amyl acetate; in methyl tert-butyl ether, with about 3 molar equivalents of silylating agent, preferably with trimethylchlorosilane, in the presence of - based on the silylating agent - an approximately stoichiometric amount of organic nitrogen base, especially triethylamine, and the product is then reacted with in a reaction with an activated carboxylic acid of formula II.

Instead of trimethylchlorosilane, other silylating agents can be used, such as, for example, bis-trimethylsilylacetamide, dichlorodimethylsilane, trichloromethylsilane or N, N'-bis-trimethylsilylurea, with bisethylsilyl trimethylsilyl being preferred among these other silylating agents. A small excess of silylating agent in excess of 3 molar equivalents-15 valents has no detrimental effect on the reaction.

When bis-trimethylsilylacetamide or N, N'-trimethylsilyl urea is used in the silylation, it is not necessary to add a base, because in this case no hydrochloric acid to be bound is present.

The silylation of a compound of formula I is carried out at temperatures between about 20-25 ° C. It can also be allowed to rise to, for example, about 40 ° C (boiling point of methylene chloride).

Combining activated ATS with silylated TACS is conveniently accomplished by adding a solution of activated ATS at temperatures between about -20 to 0 ° C, preferably between -10 and 12 ° C, slowly to the solution of silylated TACS, that the heat of reaction formed can be well dissipated, for example within a period of about 1/4 to 2 hours.

After a brief post-stirring, the reaction mixture is then worked up in a manner known per se. Thus, for example, it can be poured into water, the pH of which is kept between about 6.0 and 7.5, by adding, for example, an organic β 84829 nitrogen base, in particular triethylamine. After separation of the phases, the organic phase can be extracted once more with water in which sodium acetate has been dissolved. From the combined aqueous phases, which may be further clarified with, for example, activated carbon, Cefodizim can be precipitated as the free acid by adding an inorganic acid such as sulfuric acid, adjusting the pH to about 2.8.

If a carboxylic acid of the formula II having an amino-protecting group Rx has been used, this group must still be cleaved off in a manner known from the literature before further work-up.

After drying at slightly elevated temperature and vacuum, Cefodizim acid is thus obtained in very pure form.

In addition to achieving the aforementioned unexpected reduction of the by-product to a concentration of well below 1%, it should be noted that the already mentioned EP-A-23 453, for example in Examples 8-12, uses acylation between -70 and -72 ° C. 20 reaction temperatures. In contrast, the reaction of the invention can be carried out at temperatures between about -20 ° C and 0 ° C without causing any deterioration in quality or yield. This is considerably advantageous for the technical production of Cefodizim, since the delay times are then shorter and the need for cooling power is thus lower.

Example 1

Step 1 17.5 kg (87.1 moles) of ATS in 52 kg of dimethylacetamide with 8.95 kg (88.6 moles) of tri-ethylamine are converted to the ammonium salt at a temperature of 20-22 ° C and a stirring time of 30 minutes.

12.9 kg (68.0 moles) of p-toluenesulfochloride are dissolved in 13.2 kg of dimethylacetamide at 20-25 ° C over 30 minutes and this solution is added at -10 to -14 ° C to a suspension of 35 ATS triethylammonium salt. Within 30 minutes and stir for a further 2.5 hours.

7 84829

Step 2 23.7 kg (59.0 moles) of TACS are suspended in 212 kg of methylene chloride, 19.7 kg (181.0 moles) of trimethylchlorosilane are added at 20-25 ° C and within 20 minutes at 20-41 ° C. At 18 ° C (Boiling point of methylene chloride), 18.2 kg (180.0 moles) of triethylamine are added.

At the end of the addition, the solution is cooled very rapidly to -15 ° C and the solution of activated ATS obtained according to step 1 is added over 30 minutes at -10 to -12 ° C.

After a stirring time of 5 minutes, the reaction mixture is added over a period of 5-10 minutes to a mixture of 143 liters of water and 19.3 kg of triethylamine, keeping the pH between 6 and 7.5. After phase separation, the methylene chloride phase 15 is extracted once more with 70 liters of water in which 2.2 kg of sodium acetate 3 H2O have been dissolved and Cefodizim is mixed in the form of the free acid with 1.2 kg of activated carbon and 1.2 kg of Dicalite from the combined aqueous phases. after clarification by adding 18% sulfuric acid until the pH is 2.8. After filtration and drying at 40 [deg.] C. under a vacuum of 100 torr, 30.6 kg of Cefodizim are obtained, the purity of which is 96-97% by area by HPLC analysis.

Example 2

Step 1 corresponds to the instructions of Example 1. Step 2 23.7 kg (59.0 moles) of TACS are suspended in 212 kg of methylene chloride and 36.0 kg (177.0 moles) of bis-trimethylsilylacetamide are added. Stir for 30 minutes at 20-25 ° C, cool the clear solution to 30-15 ° C, and add the solution of activated ATS obtained in Step 1 over 30 minutes at -10 to -12 ° C. After a stirring time of 5 minutes, the reaction mixture is added over 5-10 minutes to 143 liters of water and at the same time the pH is maintained between 6.0 and 7.5 with triethylamine. After separation of the phases 35, the organic phase is extracted once more with 70 kg of water containing 2.2 kg of sodium acetate 3 β 84829 H2O. The combined aqueous phases are clarified with 1.2 kg of activated carbon and 1.2 kg of Dicalite and the product is mixed by adding 18% sulfuric acid until the pH is 2.8. After filtration and drying at 40 [deg.] C. and 100 torr under vacuum, 30.0 kg of Cefodizim * are obtained in the form of the free acid, which is 95-97% by surface area in purity by HPLC analysis.

Claims (11)

Which R2 represents hydrogen or an amino protecting group and A is hydrogen or an equivalent of an alkali or alkaline earth metal, ammonium or an organic nitrogen base, first reacted in an organic solvent and optionally in the presence of a base, with a compound of formula III. R-SO2-Hal 1 which R is p-tolyl or phenyl and Hai is chlorine, b) a compound (TACS) of the formula I HN-N-rCH, ·: 0 C00A CH2-C00A V 35 829 in which A denotes the same as above, is reacted in an organic solvent and optionally in the presence of a base with a silylating agent and c) the two products formed according to steps (a) and (b) are reacted with each other in their reaction solutions and the protecting group possibly included in the reaction product is split off. A process for the preparation of Cefodizim of formula 5B BnTs M2N Vh ° T ^ 2 B- ^ CH COOA R.HN.A_ JJ II-0CH_ 2. A process according to claim 1, characterized in that p-toluenesulfonic acid chloride is used as a compound of formula III. A process according to claim 1 or 2, characterized in that Rx and A denote hydrogen in the compound of formula II (ATS). Process according to any of claims 1-3, characterized in that the solvent used in step (a) is dimethylacetamide. Process according to any of claims 1-4, characterized in that the silylating agent is trimethylchlorosilane or bis-trimethylsilylacetamide. 20 6. A process according to claim 5, characterized in that the silylating agent is trimethylchlorosilane. Process according to claim 5 or 6, characterized in that 3 molar equivalents of silylating agent calculated on TACS are used in the process. Process according to claim 7, characterized in that the solvent used in step (b) is methylene chloride. 30 9. A process according to any of claims 1-7, characterized in that the base optionally added in the individual steps of the process is triethylamine. Process according to any of claims 1-8, characterized in that the reaction in step (a) is carried out at a temperature of about -30 to 0 ° C. i4 84829 Method according to any of claims 1-9, characterized in that the reacton in step (c) is carried out at a temperature of about -20 - 0 ° C. 5